Role of proBDNF and p75NTR in HIV-mediated axonal/dendritic degeneration

描述（由申请人提供）：人类免疫缺陷病毒-1（HIV）感染中枢神经系统可能导致神经系统综合征，称为HIV相关神经认知障碍（HAND）。HAND包括轻微的神经认知障碍和更严重形式的运动和认知障碍，称为HIV相关性痴呆（HAD）。虽然用高活性抗逆转录病毒药物治疗可以减少大脑中的HIV负荷，但由于寿命延长，HAND的患病率实际上增加了。因此，必须开发预防性和联合治疗来预防并可能逆转在这些个体中观察到的神经功能缺损。这些受试者表现出突触简化和神经元凋亡。然而，导致突触病理学的分子机制是未知的。开发有效疗法的关键是更好地理解病毒引起这些神经病理学特征的分子和细胞机制。HIV及其病毒包膜蛋白gp 120促进轴突收缩和树突简化。这些作用由脑源性神经营养因子（proBDNF）复制，并由肿瘤坏死因子家族成员p75神经营养因子受体（p75 NTR）介导。因此，我们提出了一个假设，即proBDNF通过促进p75 NTR的激活而促进HIV的神经毒性。我们已经获得了支持这一假设的初步数据。事实上，我们已经表明，HAD受试者的大脑比非HAD受试者表现出更高的proBDNF含量。此外，体外数据已经确定，HIV和gp 120介导的突触树突简化被p75 NTR拮抗剂阻断。因此，该提议将测试新的假设，即HIV通过gp 120介导的机制损伤神经元，该机制涉及proBDNF的释放，而proBDNF又通过p75 NTR介导的机制促进轴突/树突变性。将进行实验以确定p75 NTR在HIV/gp 120介导的神经毒性中的作用，以及HIV/gp 120促进proBDNF积累的细胞机制。这些包括测试参与将proBDNF加工成成熟BDNF的酶的活性。这些实验将伴随着研究，检查蛋白水解酶参与脑源性神经营养因子前体处理在死后的人脑以及在动物模型的HAD。还计划进行研究以确定proBNP与小胶质细胞激活和炎症之间的关系（如果有的话）。我们希望提供新的重要数据的作用，p75 NTR在艾滋病毒的神经毒性。这些数据将有助于设计p75 NTR拮抗剂作为艾滋病毒引起的突触简化的辅助治疗。

DESCRIPTION (provided by applicant): Human Immunodeficiency Virus-1 (HIV) infection of the central nervous system may cause a neurological syndrome termed HIV-associated neurocognitive disorders (HAND). HAND includes minor neurocognitive disorders and a more severe form of motor and cognitive impairments termed HIV associated dementia (HAD). Although treatment with highly active antiretroviral agents decreases the load of HIV in the brain, the prevalence of HAND is actually increased due to longer life. Therefore, adjunctive and combined therapies must be developed to prevent and perhaps reverse the neurologic deficits observed in these individuals. These subjects exhibit synaptic simplification and neuronal apoptosis. However, the molecular mechanisms leading to synaptic pathology are unknown. Key to developing effective therapies is a better understanding of the molecular and cellular mechanisms by which the virus causes these neuropathological features. HIV and its viral envelope protein gp120 promote axonal retraction and dendritic simplification. These effects are reproduced by the proneurotrophin brain-derived neurotrophic factor (proBDNF) and are mediated by the p75 neurotrophin receptor (p75NTR), a member of the tumor necrosis factor family. Thus, we have generated the hypothesis that proBDNF facilitates HIV neurotoxicity by promoting the activation of p75NTR. We have obtained preliminary data in support to this hypothesis. Indeed, we have shown that brains of HAD subjects exhibit a higher amount of proBDNF than non-HAD subjects. Moreover, in vitro data have determined that HIV and gp120-mediated synaptodendritic simplification is blocked by p75NTR antagonists. Thus, this proposal will test the novel hypothesis that HIV injures neurons by a gp120-mediated mechanism that involves the release of proBDNF, which in turn promotes axonal/dendritic degeneration via a p75NTR-mediated mechanism. Experiments will be carried out to establish the role of p75NTR in HIV/gp120 mediated neurotoxicity, and the cellular mechanisms whereby HIV/gp120 promotes proBDNF accumulation. These include testing the activity of enzymes involved in processing proBDNF to mature BDNF. These experiments will be accompanied by studies examining proteolytic enzymes involved in proBDNF processing in postmortem human brain as well as in animal models of HAD. Studies are also planned to establish the relationship (if any) between proBDNF and microglia activation and inflammation. We expect to provide new significant data on the role of p75NTR in HIV neurotoxicity. These data will help in the design of p75NTR antagonists as an adjunct therapy against synaptic simplification caused by HIV.